EP3489234B1 - Monocyclisches b-lactam-eisenträgerkonjugat sowie herstellungsverfahren und anwendung davon - Google Patents

Monocyclisches b-lactam-eisenträgerkonjugat sowie herstellungsverfahren und anwendung davon Download PDF

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EP3489234B1
EP3489234B1 EP17830457.2A EP17830457A EP3489234B1 EP 3489234 B1 EP3489234 B1 EP 3489234B1 EP 17830457 A EP17830457 A EP 17830457A EP 3489234 B1 EP3489234 B1 EP 3489234B1
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compund
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polar solvent
polar
mmol
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EP3489234A4 (de
EP3489234A1 (de
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Yushe Yang
Liang Tan
Qunhuan KOU
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of pharmaceutical synthesis, and more particularly, relates to a monocyclic ⁇ -lactam-siderophore conjugate as well as a method for synthesizing same and its use in the treatment of bacterial infectious diseases.
  • Gram-positive bacteria are mainly methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant enterococci (VRE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • VRE vancomycin-resistant enterococci
  • Gram-negative bacteria except for the increasing community-acquired multidrug resistant (MDR) Gram-negative bacteria such as Escherichia coli and Neisseria gonorrhoeae, hospital-acquired extensive drug resistant (XDR) and total drug resistant (TDR) Gram-negative bacteria such as Pseudomonas aeruginosa , Acinetobacter baumannii and Klebsiella pneumoniae are extremely refractory and almost no drug is available, resulting in high mortality of hospital-acquired XDR and TDR infections. Therefore, Gram-negative bacterial resistance is a crisis that has been out of control. It can be seen that the development of drugs that are effective against drug-resistant Gram-negative bacteria is a significant and imminent scientific task for scientists.
  • MDR multidrug resistant
  • XDR extensive drug resistant
  • TDR total drug resistant
  • a drug that can treat a drug-resistant negative bacterial infection should have the following characteristics: 1) it can pass through an outer membrane of the negative bacteria; 2) it is not recognized by the efflux pump and is not excreted out of the bacteria; and 3) it is not hydrolyzed by various hydrolases before reaching the target. Therefore, it is very difficult to develop drugs for multidrug-resistant negative bacteria.
  • Free iron is almost a nutrient for all microorganisms, but it is extremely low in human plasma and body fluids, only 10 -9 M, which is much lower than the needs of bacterial colonization and growth.
  • bacteria secrete various siderophores (molecules that can efficiently complex iron) to take iron from the host, transport the siderophore into the bacterial cells and release iron through the corresponding siderophore receptor on the outer membrane of the bacteria.
  • siderophores molecules that can efficiently complex iron
  • the compound has good antibacterial activity against multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii , but has less activity against the resistant Gram-negative bacteria that produce cephalosporinase (AmpC) or Class A or Class D extended-spectrum lactamases (ESBLs).
  • AmpC cephalosporinase
  • ESBLs Class D extended-spectrum lactamases
  • MC-1 has a MIC 90 of 0.5 ⁇ g/mL for multidrug-resistant Pseudomonas aeruginosa, a MIC 90 of 2 ⁇ g/mL for Escherichia coli, and a MIC 90 of 8 ⁇ g/mL for Klebsiella pneumoniae.
  • MC-1 is essentially ineffective against Acinetobacter with a MIC 90 greater than 64 ⁇ g/mL.
  • MC-1 is chemically unstable and is susceptible to hydrolysis, which limits its further research.
  • Pfizer reported compounds 4 and 5 in which a hydroxypyridone structure is introduced at the 2-position of the ⁇ -lactam ring.
  • the compounds have good activity against Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. But the activity against Acinetobacter baumannii is still low (MIC 90 > 64 ⁇ g/mL).
  • the monocyclic ⁇ -lactam-siderophore conjugates are currently in the preclinical research stage, and only a few individual compounds such as BAL30072 are in the early stages of clinical research.
  • the existing monocyclic ⁇ -lactam-siderophore conjugates have obvious deficiencies, and ubiquitously (such as the representative compound BAL30072) the antibacterial activity is not strong, and the antibacterial spectrum is not broad enough to cover the four most important multidrug-resistant Gram-negative bacteria, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. In particular, they have no antibacterial activity against important Klebsiella pneumoniae [ Antimicrob. Agents Chemother. 2010, 54, 2291-2302 ], which is a major obstacle to the clinical application of such compounds.
  • the present invention provides a novel monocyclic ⁇ -lactam-siderophore conjugate having a novel structure, a stronger antibacterial activity and a broader antibacterial spectrum.
  • the structure of such conjugate is characterized by introducing a substituent at the alpha position of the oxime ether for the first time.
  • the introduction of the substituent makes the compound of the present invention have stronger activity against Gram-negative bacteria, and more importantly, the compounds of the present invention have a broader antibacterial spectrum, and have strong activity against the four most important multidrug resistant Gram-negative bacteria, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.
  • One aspect of the present invention provides a monocyclic ⁇ -lactam-siderophore conjugate represened by formula (I), an enantiomer, a diastereomer, a racemate thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Y is H, Cl or Br.
  • R is a mono- or poly-substituted C 1-4 linear alkyl group or C 3-6 branched alkyl group
  • the substituent is preferably a hydroxyl group, -OR 1 , -SR 1 , -S(O 2 )R 1 ;
  • R is selected from the group consisting of a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, an isobutyl group, a cyclopropyl group and a vinyl group; a mono- or poly-substituted C 1-4 linear alkyl group and C 3-6 branched alkyl group, wherein the substituent is selected from the group consisting of a hydroxyl group, -OR 1 , -SR 1 and -S(O 2 )R 1 ; a phenyl group; a substituted or unsubstituted 5- or 6-membered heteroaryl ring group having 1 to 2 heteroatoms independently selected from the group consisting of N, S and O, wherein the substituent in the 5- or 6-membered heteroaryl ring group is independently selected from the group consisting of a hydroxyl group, a cyano group, -R 1 , -OR 1 , -
  • R 1 is a methyl group , an ethyl group , a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group or a cyclopropyl group.
  • R 2 and R 3 are each independently a hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group or a cyclopropyl group.
  • R 1 is a methyl group, an ethyl group, a propyl group, an isopropyl group.
  • R 2 and R 3 are each independently a hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group.
  • the representative compound of formula (I) of the present invention is one of the following compounds:
  • the pharmaceutically acceptable salt of the present invention is a pharmaceutically acceptable salt formed by a monocyclic ⁇ -lactam-siderophore conjugate of the formula (I) and an organic base or an inorganic base.
  • the pharmaceutically acceptable salt is a sodium salt, a magnesium salt, a calcium salt, an arginine salt.
  • the compound of the formula (I) of the present invention has an oximido group which may be a "cis” or a "trans”, preferably a "cis” configuration. Accordingly, the compound of the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof of the present invention further includes a cis- or trans-isomer thereof.
  • the optical isomers include its enantiomers, diastereomers, racemates, or mixtures thereof.
  • the compound of the formula (I), optical isomer thereof or pharmaceutically acceptable salt thereof of the present invention may also be present in the form of a solvate such as a hydrate, an alcoholate, a ketone compound or the like, and these solvates are also included within the scope of the invention.
  • the compound of the formula (I), its enantiomer, diastereomer, racemate or a mixture thereof or a pharmaceutically acceptable salt thereof of the present invention may also be present in the form of a tautomer, and these tautomers are also included within the scope of the invention.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by the above formula (I), optical isomer thereof or pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.
  • the monocyclic ⁇ -lactam-siderophore conjugate represented by the formula (I) or a pharmaceutically acceptable salt thereof of the present invention may be used alone, or it may be mixed with the pharmaceutically acceptable excipient (for example, a vehicle, a diluent, and the like) and formulated into a tablet, a capsule, a granule or a syrup for oral administration, or formulated into a liniment or an injection preparation for parenteral administration.
  • the pharmaceutically acceptable excipient for example, a vehicle, a diluent, and the like
  • Another aspect of the present invention provides a use of the compounds represented by the above formula (I), optical isomer thereof or pharmaceutically acceptable salt thereof for preparing a medicament for treating an infectious disease caused by bacteria, in particular, including the infectious diseases caused by sensitive and resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumonia.
  • Another aspect of the present invention provides a use of the compounds represented by the above formula (I), optical isomer thereof or pharmaceutically acceptable salt thereof or the pharmaceutical composition as described above, for preparing a medicament for treating an infectious disease caused by bacteria, in particular, including the infectious diseases caused by sensitive and resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumonia.
  • Another aspect of the present invention provides a method for treating an infectious disease caused by bacteria, in particular, including the infectious diseases caused by sensitive and resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumonia, comprising the step of administering to a subject the compound represented by the above formula (I), optical isomer thereof or pharmaceutically acceptable salt thereof or the pharmaceutical composition as described above.
  • Another aspect of the present invention provides a method for preparing said componds, but the invention is not limited to these specific preparation methods.
  • the compound of the present invention can be produced by the following method, however, the conditions of the method, for example a reactant, a solvent, an acid, a base, an amount of the compound used, a reaction temperature, reaction time, and the like are not limited to the following description.
  • the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known to those skilled in the art.
  • the compound of the formula (I) of the present invention can be produced according to the method of the reaction scheme (1).
  • X and R are defined as above;
  • R a is an amino protecting group, the protecting group is selected from the group consisting of: tert-butoxycarbonyl, p-methoxybenzyl, diphenylmethyl, trityl, benzyl, allyl;
  • R 1 is wherein R b is a hydroxyl protecting group, the protecting group is selected from the group consisting of: benzhydryl, p-methoxybenzyl or benzyl.
  • the synthetic method of compound I-1 in the above reaction scheme can refer to the literature ( Chemical & Pharmaceutical Bulletin 1990, 38(12), 3476-3479 , Bioorg. Med. Chem. 15 (2007) 6716-6732 ); the synthetic method of compound 1-4 may refer to the literature ( WO 2008/116813 A2 , WO 2013/110643 A1 ); the synthetic method of the key intermediate 1-2 may be selected from one of the following methods:
  • R is a C 1-4 linear alkyl group or a C 1-4 alkenyl group or a C 3-4 cycloalkyl group
  • the synthetic method of the compound a-1 in the above reaction scheme can refer to the document US/4883879A .
  • R is a C 1-4 linear alkyl group or a C 1-4 alkenyl group or a C 3-4 cycloalkyl group
  • R is a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group; and R 1 and R 2 are each independently: a hydrogen; or a C 1-6 linear alkyl group, a C 3-6 ;branched alkyl group or a C 3-6 cycloalkyl group;
  • R is a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group;
  • the synthetic method of the compound c-9 in the above scheme can refer to the literature ( WO2012073138A1 ).
  • R is a hydroxyl group, an amino group, -OR 1 , -NR 2 R 3 ; -R 1 is a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group; and R 2 and R 3 are each independently: a hydrogen or a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group;
  • R is a hydroxyl group, an amino group, -OR 1 , -SR 1 , -NR 2 R 3 ;
  • R 1 is a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group;
  • R 2 and R 3 are each independently: a hydrogen or a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group;
  • R is a C 1-6 linear alkyl group, a C 3-6 branched alkyl group, a C 3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl ring group having 1 to 4 hetero atoms independently selected from the group consisting of N, S and O;
  • R is a C 1-6 linear alkyl group, a C 3-6 branched alkyl group, a C 3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl ring group having 1 to 4 hetero atoms independently selected from the group consisting of N, S and O.
  • the synthetic method of compound f-1 can refer to the method of compound c-10.
  • R is a hydroxyl group, an amino group, -OR 1 , -NR 2 R 3 ;
  • R 1 is a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group;
  • R 2 and R 3 are each independently: a hydrogen or a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group;
  • R is a C 1-6 linear alkyl group, a C 3-6 alkenyl group, a C 3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl ring group having 1 to 4 hetero atoms independently selected from the group consisting of N, S and O;
  • R is -OR 1 , -SR 1 , -NR 2 R 3 ;
  • R 1 is a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group;
  • R 2 and R 3 are each independently: a hydrogen, a C 1-6 linear alkyl group, a C 3-6 branched alkyl group or a C 3-6 cycloalkyl group;
  • the inventor synthesized a series of compounds through extensive studies. By performing the antibacterial activity screening and pharmacokinetic screening, the inventor firstly discovered that the compounds of the following formula (I) possess potent antibacterial activity and good harmacokinetic properties. In particular, these compounds are suitable as the drug for anti-infective treatment. Based on these studies, the inventor completed the present invention.
  • a white solid compound a-3-2 (720 mg, yield 67.8%.) was prepared from compound a-2 (1.0 g, 2.05 mmol) and 1M of ethylmagnesium bromide (10 mL, 10 mmol).
  • a white solid compound a-4-2 (160 mg, yield 61.9%) was prepared from compound a-3-2 (200 mg, 0.39 mmol), N-hydroxyphthalimide (78 mg, 0.46 mmol), triphenylphosphine (262.3 mg, 0.97 mmol) and diethyl azodicarboxylate (0.15 mL, 0.97 mmol).
  • a white solid compound a-3-3 (800 mg, yield 75.7%.) was prepared from compound a-2 (1.0 g, 2.05 mmol), 1M of vinyl magnesium bromide (10mL, 10mmol).
  • a white solid compound a-4-3 (661 mg, yield 64.5%) was prepared from compound a-3-3 (800 mg, 1.55 mmol), N-hydroxyphthalimide (304 mg, 1.9 mmol), triphenylphosphine (839 mg, 3.2 mmol) and diethyl azodicarboxylate (0.5 mL, 3.2 mmol).
  • a white solid compound a-5-3 crude product (476mg) was prepared from compound a-4-3 (660 mg, 1 mmol), 85% hydrazine hydrate (0.12 mL, 2 mmol), the crude product was directly used for the next reaction.
  • a white solid compound a-3-4 (477 mg, yield 73.2%) was prepared from compound a-2 (600 mg, 1.23 mmol), 0.5M of cyclopropyl magnesium bromide (9.6 mL, 4.8 mmol).
  • a pale yellow solid compound a-4-4 (290 mg, yield 47.7%) was prepared from compound a-3-4 (477 mg, 0.9 mmol), N-hydroxyphthalimide (440 mg, 2.7 mmol), triphenylphosphine (708 mg, 2.7 mmol) and diisopropyl azodicarboxylate (0.54 mL, 2.7 mmol).
  • dichlorobis(4-methylisopropylphenyl)ruthenium (II) (18 mg, 0.03 mmol) and (1S,2S)-(-)-N-(p-methylbenzenesulfonyl)-1,2-diphenylethylenediamine (22 mg, 0.06 mmol) were dissolved in dry N,N-dimethylformamide (5 mL), and triethylamine (6.19 mg) was added thereto and the mixture was stirred at room temperature for 1 hour.
  • a white solid compound b-5 (850 mg, yield 76.8%) was prepared from compound b-3 (1.1 g, 2.2 mmol), dichlorobis(4-methylisopropylphenyl)ruthenium (II) (22 mg, 0.036 mmol) and (1R,2R)-(-)-N-(p-methylbenzenesulfonyl)-1,2-diphenylethylenediamine (26.4 mg, 0.072 mmol).
  • the compound c-10 (31.8 g, 99.6 mmol) was dissolved in 120 mL of tetrahydrofuran, and 350 mL of water was added thereto, and the reactant was in a suspended state.
  • Sodium hydrogen sulfite (15.5 g, 149.4 mmol) was added, and the reaction solution changed from clear to turbid, and was stirred for 1 h in an ice bath.
  • the compound c-11 (14.1 g, 40.7 mmol) was dissolved in 150 mL of a dry solution of 2M methanol in hydrochloric acid, and reacted at room temperature for 10 hours. After the starting material disappeared as monitored by TLC, methanol was evaporated under reduced pressure, and the residue was added with saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (100 mL ⁇ 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • a pale yellow solid compound c-2 (1.5 mg, yield 66.5%) was prepared from compound c-1 (1.79 g, 3.26 mmol), N-hydroxyphthalimide (1.60 g, 9.8 mmol), triphenylphosphine (2.58 g, 9.8 mmol) and diisopropyl azodicarboxylate (1.6 mL, 9.8 mmol).
  • step 4 of Preparation 1 324 mg of a white solid compound c-3 crude product was prepared from compound c-2 (500 mg, 0.72 mmol), 85% hydrazine hydrate (0.04 mL, 0.72 mmol), the crude product was directly used for the next reaction.
  • a white solid compound c-6 (540mg, crude product was directly used for the next reaction) was prepared from the above c-5 (2.15 g, 3.08 mmol), N-hydroxyphthalimide (1.51 g, 9.23 mmol), triphenylphosphine (2.42 g, 9.23 mmol) and diisopropyl azodicarboxylate (1.5 mL, 9.23 mmol) and 85% hydrazine hydrate (0.17 mL, 2.84 mmol).
  • a white solid compound c-8 (400mg, crude product was directly used for the next reaction) was prepared from the above c-7 (535 mg, 0.98 mmol), N-hydroxyphthalimide (480 mg, 2.94 mmol), triphenylphosphine (769 mg, 2.94 mmol) and diisopropyl azodicarboxylate (0.58 mL, 2.94mmol) and 85% hydrazine hydrate (0.17 mL, 2.84mmol).
  • Trimethylsulfoxonium iodide (2.42 g, 11 mmol) was dissolved in 20 mL of dry dimethyl sulfoxide, 10 mL of tetrahydrofuran was added. 60% sodium hydride (440 mg, 11 mmol) was added under ice bath and the mixture was stirred for 1 hour.
  • Compound c-10 (3.2 g, 10 mmol) was dissolved in dry dimethyl sulfoxide (20 mL), and slowly added dropwise to the above reaction solution in an ice bath. Thereafter, the reaction solution was slowly warmed to room temperature, and reacted for 2 h.
  • a pale yellow solid compound d-3 (170mg, 81.2%) was prepared from compound d-2 (150 mg, 0.41 mmol), N-hydroxyphthalimide (80 mg, 0.49 mmol), triphenylphosphine (160 mg, 0.62 mmol) and diethyl azodicarboxylate (0.09 mL, 0.62 mmol).
  • reaction solution was added with 50 mL of water, 20 mL of saturated sodium bicarbonate solution and 50 mL of dichloromethane, and a dichloromethane phase was separated, which was further washed with 50 mL of a saturated aqueous solution of sodium thiosulfate, and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • step 5 of Preparation 6 compound d-4 (1.01 g, 1.92 mmol) was removed of its protection group by reacting with boron trichloride (4.6 mL, 4.6 mmol) to give the title compound d-5 (1.07 g, crude, directly used for the next reaction).
  • a white solid compound d-6 (700mg, yield in two steps: 53.7%) was prepared from the above crude d-5 (1.07 g) and diphenyldiazomethane (1.86 g, 9.6 mmol).
  • a white solid compound d-7 (400mg, crude, directly used for the next reaction) was prepared from compound d-6 (700 mg, 1.03 mmol) and 85% hydrazine hydrate (0.07 mL, 1.13mmol).
  • a white solid compound d-8 (3.2 g, 80.3%) was prepared from compound d-1 (3.8 g, 11.4 mmol) and m-chloroperoxybenzoic acid (7.05 g, 34.2 mmol).
  • the compound d-8 (3.0 g, 8.58 mmol) was dissolved in 20 mL of dioxane, a 20% aqueous sodium thiomethoxide solution (14.9 mL, 42.9 mmol) was added thereto, and the reaction was carried out overnight at room temperature to precipitate a white solid. After the raw materials disappeared as monitored by TLC, the reaction solution was filtered, and the white solid was rinsed with water (10 mL), and then rinsed with 5 mL of petroleum ether and dried at 50 °C in vacuo for 10 hours to give a white solid compound d-9-1 (1.43 g, 41.9%).
  • step 5 of Preparation 6 compound d-9-1 (7.2 g, 18.11 mmol) was removed of its protection group by reacting with boron trichloride (45.3 mL, 45.3 mmol) to give the title compound d-10-1 (8.5 g, crude, directly used for the next reaction).
  • a white solid compound d-11-1 (4.3 g, yield in two steps 43.2%) was prepared from the above crude d-10-1 (8.5 g) and diphenyldiazomethane (21.1 g, 108.7 mmol).
  • a pale yellow solid compound d-12-1 (366 mg, 59.9%) was prepared from compound d-11-1 (484 mg, 0.88 mmol), N-hydroxyphthalimide (215 mg, 1.32 mmol), triphenylphosphine (461 mg, 1.76 mmol) and diisopropyl azodicarboxylate (0.27 mL, 1.76 mmol).
  • a white solid compound d-13-1 (206 mg, 69.1%) was prepared from compound d-12-1 (366 mg, 0.53 mmol) and 85% hydrazine hydrate (0.04 mL, 0.53 mmol).
  • Isopropyl mercaptan (2.66 mL, 28.6 mmol) was dissolved in 20 mL of dioxane, and cooled to 0 °C in an ice bath. 60% sodium hydride (1.14 g, 28.6 mmol) was added at low temperature and the reaction was carried out for 30 min.
  • the compound d-8 (2.0 g, 5.72 mmol) was dissolved in 10 mL of dioxane, and the solution was added dropwise to the above reaction solution, the reaction was carried out for 1 hour. Water (20 mL) was added to the reaction system to precipitate a white solid.
  • step 5 of Preparation 6 compound d-9-2 (2.17 g, 5.1 mmol) was removed of its protection group by reacting with boron trichloride (12.7 mL, 12.7 mmol) to give the title compound d-10-2 (2.5 g, crude, directly used for the next reaction).
  • a white solid compound d-11-2 (1.03 g, yield in two steps: 34.9%) was prepared from the above crude d-10-2 (2.5 g) and diphenyldiazomethane (5.94 g, 30.6 mmol).
  • reaction solution was warmed to room temperature, extracted with 100 mL of ethyl acetate, and then washed sequentially with a saturated aqueous solution of sodium bicarbonate (20 mL ⁇ 3), water (20 mL ⁇ 2) and 20 mL of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated.
  • a white solid compound d-13-2 (314 mg, 66.0%) was prepared from compound d-12-2 (580 mg, 0.81 mmol) and 85% hydrazine hydrate (0.06 mL, 0.81 mmol).
  • a pale yellow solid compound e-2 (1.0 g, 57.6%) was prepared from compound e-1 (1.24 g, 3.41 mmol), N-hydroxyphthalimide (836 mg, 5.12 mmol), triphenylphosphine (2.22 mg, 8.52 mmol) and diethyl azodicarboxylate (1.2 mL, 8.52 mmol).
  • a white solid compound e-3 (0.53 g, 52.9%) was prepared from compound e-2 (1.1 g, 2.16 mmol) and m-chloroperoxybenzoic acid (1.1 g, 5.41 mmol).
  • step 5 of Preparation 6 compound e-3 (820 mg, 1.56 mmol) was removed of its protection group by reacting with boron trichloride (3.9 mL, 3.9 mmol) to give the title compound e-4 (880 mg, crude, directly used for the next reaction).
  • a white solid compound e-5 (650 mg, yield in two steps: 61.6%) was prepared from the above crude e-4 (880 mg) and diphenyldiazomethane (1.51 g, 7.8 mmol).
  • a white solid compound e-6 (210 mg, crude, directly used for the next reaction) was prepared from compound e-5 (340 mg, 0.50 mmol) and 85% hydrazine hydrate (0.04 mL, 0.60 mmol).
  • a pale yellow solid compound f-3 (785 mg, 47.6%) was prepared from compound f-2 (1.23 g, 2.9 mmol), N-hydroxyphthalimide (0.71 g, 4.4 mmol), triphenylphosphine (1.52 g, 5.8 mmol) and diethyl azodicarboxylate (0.9 mL, 5.8 mmol).
  • a white solid compound f-4 (680 mg, 86.1%) was prepared from compound f-3 (770 mg, 1.35 mmol) and m-chloroperoxybenzoic acid (934 mg, 4.05 mmol).
  • a white solid compound f-5 (450 mg, 85.3%) was prepared from compound f-4 (680 mg, 1.16 mmol) and 85% hydrazine hydrate (0.08 mL, 1.16 mmol).
  • a pale yellow solid compound f-3-1 (4.07 g, 80.4%) was prepared from compound f-2-1 (3.85 g, 8.4 mmol), N-hydroxyphthalimide (1.65 g, 10.1 mmol), triphenylphosphine (3.27 g, 12.6 mmol) and diethyl azodicarboxylate (1.8 mL, 12.6 mmol).
  • a white solid compound f-4-1 (3.7 g, 88.5%) was prepared from compound f-3-1 (4.07 g, 6.75 mmol) and m-chloroperoxybenzoic acid (4.13 g, 20.26 mmol).
  • a white solid compound f-5-1 (230 mg, crude, directly used for the next reaction) was prepared from compound f-4-1 (530 mg, 0.86 mmol) and 85% hydrazine hydrate (0.07 mL, 1.03 mmol).
  • a pale yellow solid compound f-3-2 (0.8 g, 36.3%) was prepared from compound f-2-2 (1.68 g, 3.61 mmol), N-hydroxyphthalimide (1.77 g, 10.85 mmol), triphenylphosphine (4.69 g, 18.05 mmol) and diethyl azodicarboxylate (2.6 mL, 18.05 mmol).
  • a white solid compound f-4-2 (328 mg, 40.0%) was prepared from compound f-3-2 (800 mg, 1.31 mmol) and m-chloroperoxybenzoic acid (825 mg, 3.93 mmol).
  • a white solid compound f-5-2 (176 mg, 65.4%) was prepared from compound f-4-2 (340 mg, 0.54 mmol) and 85% hydrazine hydrate (0.04 mL, 0.60 mmol).
  • the thiophene (2.1 mL, 26.3 mmol) was dissolved in 10 mL of dry tetrahydrofuran, cooled to -78 °C.
  • a solution of 2.4 M n-butyllithium in n-hexane (3.3 mL, 7.92 mmol) was slowly added dropwise at low temperature, and the mixture was reacted at low temperature for 30 min.
  • 10 mL of a solution of j-1 (1.0 g, 2.63 mmol) in tetrahydrofuran was slowly added dropwise. Thereafter, the mixture was reacted for 3 hours, then the starting material disappeared as monitored by TLC.
  • a yellow compound f-3-3 (2.0 g, 47.6%) was prepared from compound f-2-3 (3.2 g, 6.9 mmol), N-hydroxyphthalimide (3.3 g, 20.7 mmol), triphenylphosphine (5.34 g, 20.7 mmol) and diethyl azodicarboxylate (4.1 mL, 20.7 mmol).
  • a white solid compound f-4-3 (1.38 g, 67.4%) was prepared from compound f-3-3 (2.0 g, 3.28 mmol) and m-chloroperoxybenzoic acid (2.3 g, 9.8 mmol).
  • a white solid compound f-5-3 (0.98 g, 82.5 %) was prepared from compound f-4-3 (1.5 g, 2.45 mmol) and 85% hydrazine hydrate (0.18 mL, 2.57 mmol).
  • a white solid compound f-6 (4.7 g, 45.3%) was prepared from compound f-1 (10 g, 26.4 mmol) and trimethylsulfoxonium iodide (6.4 g, 29.0 mmol), 60% sodium hydride (1.16 g, 29.0 mmol).
  • a yellow compound f-8-1 (1.0 g, 86.1%) was prepared from compound f-7-1 (880 mg, 1.94 mmol), N-hydroxyphthalimide (475 mg, 2.91 mmol), triphenylphosphine (756 mg, 2.91 mmol) and diisopropyl azodicarboxylate (0.36 mL, 2.91 mmol).
  • a white solid compound f-9-1 (900 mg, 87.6%) was prepared from compound f-8-1 (1.0 g, 1.67 mmol) and m-chloroperoxybenzoic acid (1.03 g, 5.01 mmol).
  • a white solid compound f-10-1 (590 mg, 83.4%) was prepared from compound f-9-1 (900 mg, 1.46 mmol) and 85% hydrazine hydrate (0.10 mL, 1.61 mmol).
  • the compound f-6 (1.64 g, 4.17 mmol) was dissolved in methanol (30 mL), and a 20% aqueous sodium thiomethoxide solution (14 mL, 41.7 mmol) was added thereto, and the mixture was reacted at room temperature for 1 h, then the starting material disappeared as monitored by TLC.
  • the reaction solution was extracted with ethyl acetate (100 mL) and water (20 mL) and the aqueous layer was further extracted with 50 mL of ethyl acetate.
  • the organic phase was combined, washed 5 times with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • a yellow oil f-8-2 (1.2g, 83.8%) was prepared from compound f-7-2 (1.08 g, 2.44 mmol), N-hydroxyphthalimide (517 mg, 3.17 mmol), triphenylphosphine (1.28 g, 4.88 mmol) and diisopropyl azodicarboxylate (0.75 mL, 4.88 mmol).
  • a white solid compound f-9-2 (810mg, 62.5%) was prepared from compound f-8-2 (1.2 g, 2.04 mmol) and m-chloroperoxybenzoic acid (2.6 g, 12.3 mmol).
  • a white solid compound f-10-2 (636 mg, 82.5%) was prepared from compound f-9-2 (970 mg, 1.53 mmol) and 85% hydrazine hydrate (0.11 mL, 1.68 mmol).
  • the compound d-1 (6.6 g, 19.8 mmol) was dissolved in 100 mL of dioxane, and 50 mL of a 2 M aqueous sulfuric acid solution was added dropwise at room temperature. Thereafter, the mixture was reaced at 45 °C for 8 hours, then the starting material disappeared as monitored by TLC.
  • the reaction solution was neutralized with 1M sodium hydroxide solution, and the resultant was extracted with ethyl acetate (100 mL ⁇ 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • a pale yellow solid compound k-3 (6.4 g, 82.7%) was prepared from compound k-2 (5.9 g, 12.67 mmol), N-hydroxyphthalimide (2.48 g, 15.2 mmol), triphenylphosphine (4.98 g, 19.0 mmol) and diethyl azodicarboxylate (2.99 mL, 19.0 mmol).
  • the compound k-4 (3.0 g, 6.04 mmol) was dissolved in dichloromethane (40 mL), cooled to 0 °C in an ice bath, and then diethylamine trifluorosulfide (1.7 mL, 12.08 mmol) was added dropwise. Thereafter, the ice bath was removed and the reaction system returned to room temperature. The reaction was carried out for 18 hours, then the starting material disappeared as monitored by TLC. 10 mL of saturated aqueous sodium bicarbonate solution was slowly added dropwise in an ice bath, and then 20 mL of water was added to separate layers.
  • a white solid compound k-6 (1.36 g, 85.6%) was prepared from compound k-5 (1.54 g, 3.09 mmol) and m-chloroperoxybenzoic acid (1.92 g, 9.26 mmol).
  • step 5 of Preparation 6 compound k-6 (1.36 g, 2.65 mmol) was removed of its protection group by reacting with boron trichloride (7.8 mL, 7.8 mmol) to give the title compound k-7 (1.4 g, crude, directly used for the next reaction).
  • a white solid compound k-8 (720 mg, yield in two steps: 40.7%) was prepared from the above crude k-7 (1.4 g) and diphenyldiazomethane (2.56 g, 13.25 mmol).
  • a white solid compound k-9 (260mg, 77.6%) was prepared from compound k-8 (416 mg, 0.62 mmol) and 85% hydrazine hydrate (0.04 mL, 0.68 mmol).
  • a white solid compound g-1-1 (1.29 g, 82.9%) was prepared from compound f-2 (1.5 g, 3.54 mmol) and m-chloroperoxybenzoic acid (2.4 g, 10.62 mmol).
  • step 5 of Preparation 6 compound g-1-1 (6.9 g, 15.7 mmol) was removed of its protection group by reacting with boron trichloride (39 mL, 39.2 mmol) to give the title compound g-2-1 (7.5 g, crude, directly used for the next reaction).
  • a white solid compound g-3-1 (4.26 g, yield in two steps: 51.0%) was prepared from the above crude g-2-1 (7.5 g) and diphenyldiazomethane (15.2 g, 78.5 mmol).
  • the compound g-3-1 (5.5 g, 10.3 mmol) was dissolved in a mixed solvent of dichloromethane 60 mL and dimethyl sulfoxide 60 mL. 11.1 mL of triethylamine was added thereto, and the mixture was cooled to 0 °C in an ice water bath. Sulfur trioxide pyridine (8.3 g, 51.7 mmol) was added in three batchs and the mixture was reacted at low temperature for 2 hours.
  • a white solid compound g-6-1 (600 mg, Yield 94.0%) was prepared from compound g-4-1 (640 mg, 1.2 mmol), dichlorobis(4-methylisopropylphenyl)phosphonium (II) (21.8 mg, 0.035 mmol) and (1S,2S)-(-)-N-(p-methylbenzenesulfonyl)-1,2-diphenylethylenediamine (25.8 mg, 0.069 mmol).
  • a white solid compound g-10-1 (2.36 g, yield 82.5%) was prepared from compound g-8-1 (3.54 g, 5.23 mmol) and 85% hydrazine hydrate (0.34 mL, 5.75 mmol).
  • a white solid compound g-5-1 (520 mg, 89.8%) was prepared from compound g-4-1 (580 mg, 1.15 mmol), dichlorobis(4-methylisopropylphenyl)phosphonium (II) (21.8 mg, 0.035 mmol) and (1R,2R)-(-)-N-(p-methylbenzenesulfonyl)-1,2-diphenylethylenediamine (25.8 mg, 0.069 mmol).
  • a yellow solid compound g-7-1 (840 mg, 78.6%) was prepared from compound g-5-1 (840 mg, 1.58 mmol), N-hydroxyphthalimide (258 mg, 1.58 mmol), tributylphosphine (0.58 mL, 2.37 mmol) and diisopropyl azodicarboxylate (0.32 mL, 2.37 mmol).
  • a white solid compound g-9-1 (600 mg, yield 88.5%)was prepared from compound g-7-1 (840 mg, 1.24 mmol) and 85% hydrazine hydrate (0.08 mL, 1.36 mmol).
  • a yellow solid compound g-11-1 (2.57 g, yield 47.8%) was prepared from compound d-11-1 (5.4 g, 9.8 mmol) and sulphur trioxide pyridine (4.7 g, 29.4 mmol).
  • 1 H NMR 400 MHz, chloroform-d) ⁇ 7.77 (s, 1H), 7.48 - 7.27 (m, 21H), 6.35 (s, 1H), 6.23 (s, 1H), 4.01 (s, 2H), 1.91 (s, 3H).
  • compound g-11-1 (1.8 g, 3.29 mmol) was dissolved in dry N,N-dimethylformamide (15 mL), then methyl t-butyl ether (10 mL) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (II) (62 mg, 0.1 mmol) were sequentially added, during which, the air was exchanged for three times. 1.48 mL of triethylamine and 1.09 mL of formic acid were mixed, and added to the above reaction solution once.
  • a colorless oil g-15-1 (341 mg, 42.3%) was prepared from compound g-13-1 (640 mg, 1.16 mmol), N-hydroxyphthalimide (1.9 g, 11.6 mmol), tributylphosphine (1.6 mL, 6.96 mmol) and diisopropyl azodicarboxylate (0.86 mL, 6.96 mmol).
  • a white solid compound g-17-1 (287 mg, 80.7%) was prepared from compound g-15-1 (439 mg, 0.63 mmol) and 85% hydrazine hydrate (0.05 mL, 0.65 mmol).
  • a white solid g-12-1 (300 mg, yield 23.9%) was prepared from compound g-11-1 (1.25 g, 2.28 mmol) and (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (II) (44 mg, 0.07 mmol).
  • a colorless oil g-14-1 (648 mg, 60.6%) was prepared from compound g-12-1 (848 mg, 1.54 mmol), N-hydroxyphthalimide (2.5 g, 15.4 mmol), tributylphosphine (2.1 mL, 9.24 mmol) and diisopropyl azodicarboxylate (1.1 mL, 9.24 mmol).
  • a white solid compound g-16-1 (390 mg, 82.2%) was prepared from compound g-14-1 (583 mg, 0.84 mmol) and 85% hydrazine hydrate (0.06 mL, 0.84 mmol).
  • a pale yellow solid compound 1-3-2 (400 mg, yield 47%) was prepared from compound b-6 (480 mg, 0.92 mmol) and I-1 (373 mg, 0.92 mmol).
  • a white solid compound 1-5-2 (300 mg, yield 61.6%) was prepared from compound 1-3-2 (400 mg, 0.44 mmol) and 1-4 (126 mg, 0.60 mmol).
  • a white solid compound 2 (136 mg, yield: 94.6%) was prepared from compound 1-5-2 (296 mg, 0.27 mmol) and trifluoroacetic acid (0.95 mL, 13.6 mmol).
  • a pale yellow solid compound 1-3-3 (300 mg, 0.58 mmol) and I-1 (240 mg, 0.58 mmol).
  • a white solid compound 1-5-3 (200 mg, yield 56.4%) was prepared from compound 1-3-3 (290 mg, 0.32 mmol) and 1-4 (100 mg, 0.48 mmol).
  • a white solid compound 3 (60 mg, yield 83%) was prepared from compound 1-5-3 (150 mg, 0.14 mmol) and trifluoroacetic acid (1 mL, 14 mmol).
  • a pale yellow solid compound 1-3-4 (300 mg, yield 68.8%) was prepared from compound a-5-2 (250 mg, 0.47 mmol) and I-1 (194 mg, 0.47 mmol).
  • a white solid compound 1-5-4 (250 mg, yield 69.7%) was prepared from compound 1-3-4 (300 mg, 0.32 mmol) and 1-4 (95 mg, 0.45 mmol).
  • a white solid compound 4 (75 mg, yield 61%) was prepared from compound I-5-4 (250 mg, 0.22 mmol) and trifluoroacetic acid (0.8 mL, 11 mmol).
  • a pale yellow solid compound 1-3-5 (480 mg, yield 60.9%) was prepared from compound a-5-3 (450 mg, 0.85 mmol) and I-1 (350 mg, 0.85 mmol).
  • a white solid compound 1-5-5 (300 mg, yield 51.5%) was prepared from compound 1-3-5 (480 mg, 0.52 mmol) and 1-4 (163 mg, 0.78 mmol).
  • a white solid compound 5 (100 mg, yield 68%) was prepared from compound 1-5-5 (300 mg, 0.27 mmol) and trifluoroacetic acid (1 mL, 13.5 mmol).
  • a white solid compound 1-5-6 (340 mg, yield 73.2%) was prepared from compound 1-3-6 (390 mg, 0.41 mmol) and 1-4 (126 mg, 0.60 mmol).
  • a white solid compound 6 (70 mg, yield 44.7%) was prepared from compound 1-5-6 (323 mg, 0.28 mmol) and trifluoroacetic acid (1.1 mL, 14 mmol).
  • a pale yellow solid compound 1-3-7 (380 mg, yield 38.1%) was prepared from compound e-1 (570 mg, 1.07 mmol) and I-1 (258 mg, 0.62 mmol).
  • a white solid compound 1-5-7 (120 mg, yield 26.1%) was prepared from compound 1-3-7 (380 mg, 0.41 mmol) and 1-4 (128 mg, 0.61 mmol).
  • a white solid compound 7 (46 mg, yield 76.3%) was prepared from compound 1-5-7 (120 mg, 0.11 mmol) and trifluoroacetic acid (0.4 mL, 5 mmol).
  • a white solid compound 1-3-8 (360 mg, yield 65.3%) was prepared from compound g-7 (320 mg, 0.58 mmol) and I-1 (230 mg, 0.55 mmol).
  • a white solid compound 1-5-8 (204 mg, yield 84.6%) was prepared from compound 1-3-8 (200 mg, 0.21 mmol) and 1-4 (67 mg, 0.31 mmol).
  • a white solid compound 8 (80 mg, yield 82.7%) was prepared from compound 1-5-8 (196 mg, 0.17 mmol) and trifluoroacetic acid (0.6 mL, 8.6 mmol).
  • a pale yellow solid compound 1-3-9 (200 mg, yield 41.3%) was prepared from compound c-3 (286 mg, 0.51 mmol) and I-1 (210 mg, 0.51 mmol).
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 8.64 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.62 - 7.13 (m, 35H), 6.96 (s,1H), 6.84 (s, 1H), 6.68 (s, 1H), 5.55 (s, 1H), 3.60 (s, 3H).
  • a white solid compound 1-5-9 (140 mg, yield 36.4%) was prepared from compound 1-3-9 (320 mg, 0.33 mmol) and 1-4 (105 mg, 0.50 mmol).
  • a white solid compound 9 (92 mg, yield 83.9%). was prepared from compound 1-5-9 (220 mg, 0.19 mmol) and trifluoroacetic acid (0.67 mL, 9.5 mmol).
  • a pale yellow solid compound 1-3-10 (370 mg, yield 70.1%) was prepared from compound c-6 (340 mg, 0.48 mmol) and I-1 (197 mg, 0.48 mmol).
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 8.63 (s, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.60 - 7.13 (m, 45H), 7.02 - 6.97 (m, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 6.70 (s, 1H), 5.72 (s, 1H).
  • a white solid compound 1-5-10 (321 mg, yield 76.0%) was prepared from compound 1-3-10 (360 mg, 0.32 mmol) and 1-4 (102 mg, 0.48 mmol).
  • a white solid compound 10 (100 mg, yield: 80.0%) was prepared from compound 1-5-10 (290 mg, 0.22 mmol) and trifluoroacetic acid (0.78 mL, 11.1 mmol).
  • a white solid compound 1-3-11 (160 mg, yield: 18.7%) was prepared from compound c-8 (500 mg, 0.89 mmol) and I-1 (277 mg, 0.67 mmol).
  • a white solid compound 1-5-11 120 mg, yield: 62.4%. was prepared from compound 1-3-11 (160 mg, 0.17 mmol) and 1-4 (53 mg, 0.25 mmol).
  • a white solid compound 11 (43 mg, yield 77.8%) was prepared from compound 1-5-11 (110 mg, 0.10 mmol) and trifluoroacetic acid (0.35 mL, 5.0 mmol).
  • a pale yellow solid compound 1-3-12 (236 mg, yield: 65.1%) was prepared from compound e-6 (210 mg, 0.38 mmol) and I-1 (144 mg, 0.34 mmol).
  • a white solid compound 1-5-12 (294 mg, yield: 94.1%) was prepared from compound 1-3-12 (260 mg, 0.27 mmol) and 1-4 (87 mg, 0.41 mmol).
  • a white solid compound 12 (100 mg, yield 68.9%) was prepared from compound 1-5-12 (294 mg, 0.26 mmol) and trifluoroacetic acid (0.9 mL, 12.9 mmol).
  • a pale yellow solid compound 1-3-13 (570 mg, yield: 70.2%) was prepared from compound f-5-1 (448 mg, 0.92 mmol) and I-1 (342 mg, 0.83 mmol).
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 8.89 (s, 1H), 8.07 (s, 1H), 7.41 - 7.15 (m, 24H), 6.97 - 6.84 (m, 5H), 6.56 (s, 1H), 5.14 (s, 2H), 5.05 (s, 2H), 3.74 (s, 3H), 3.73 (s, 3H).
  • a white solid compound 1-5-13 (240 mg, yield: 65.7%) was prepared from compound 1-3-13 (300 mg, 0.34 mmol) and 1-4 (92.6 mg, 0.44 mmol).
  • a white solid compound 13 (100 mg, yield: 80.1%) was prepared from compound 1-5-13 (230 mg, 0.21 mmol) and trifluoroacetic acid (1.5 mL, 21 mmol).
  • a pale yellow solid compound 1-3-14 (400 mg, yield 44.8%) was prepared from compound f-5-2 (495 mg, 1.00 mmol) and I-1 (370 mg, 0.90 mmol).
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 8.69 (s, 1H), 8.05 (s, 1H), 7.79 - 7.74 (m, 1H), 7.42 - 7.20 (m, 20H), 6.96 - 6.91 (m, 2H), 6.86 - 6.80 (m, 2H), 6.75 (s, 1H), 6.70 (s, 1H), 5.35 - 5.10 (m, 2H), 5.07 (s, 2H), 3.75 (s, 3H), 3.73 (s, 3H).
  • a white solid compound 1-5-14 (230 mg, yield 47.4%) was prepared from compound 1-3-14 (400 mg, 0.45 mmol) and 1-4 (141 mg, 0.67 mmol).
  • a white solid compound 14 (94 mg, yield: 75.5%) was prepared from compound 1-5-14 (225 mg, 0.21 mmol) and trifluoroacetic acid (1.5 mL, 21 mmol).
  • a pale yellow solid 1-3-15 (474 mg, yield 58.4 %) was prepared from compound f-5-3 (450 mg, 0.91 mmol) and I-1 (339 mg, 0.81 mmol).
  • a white solid compound 1-5-15 (500 mg, yield 91.4%) was prepared from compound 1-3-15 (450 mg, 0.51 mmol) and 1-4 (159 mg, 0.76 mmol).
  • a white solid compound 15 (73 mg, yield 43.9%) was prepared from compound 1-5-15 (300 mg, 0.28 mmol) and trifluoroacetic acid (2.0 mL, 27.7 mmol).
  • a white solid compound 1-5-16 (310 mg, yield: 65.9%) was prepared from compound 1-3-16 (380 mg, 0.40 mmol) and 1-4 (124 mg, 0.59 mmol).
  • a white solid compound 16 (140 mg, yield 90.1%) was prepared from compound 1-5-16 (285 mg, 0.25 mmol) and trifluoroacetic acid (1.8 mL, 25 mmol).
  • a pale yellow solid compound 1-5-17 (400 mg, yield 92.5%) was prepared from compound 1-3-17 (362 mg, 0.37 mmol) and 1-4 (115 mg, 0.55 mmol).
  • a white solid compound 17 (160 mg, yield: 90.9%) was prepared from compound 1-5-17 (343 mg, 0.29 mmol) and trifluoroacetic acid (2.1 mL, 29 mmol).
  • a pale yellow solid compound 1-3-18 (990 mg, yield 92.1 %) was prepared from compound f-10-1 (590 mg, 1.22 mmol) and I-1 (479 mg, 1.16 mmol).
  • a white solid compound 1-5-18 (525 mg, yield 88.1%) was prepared from compound 1-3-18 (490 mg, 0.56 mmol) and 1-4 (175 mg, 0.83 mmol).
  • a white solid compound 18 (153 mg, yield 79.4%) was prepared from compound 1-5-18 (350 mg, 0.33 mmol) and trifluoroacetic acid (2.3 mL, 33 mmol).
  • a white solid compound 1-5-19 (390 mg, yield 68.5%) was prepared from compound 1-3-19 (470 mg, 0.52 mmol) and 1-4 (165 mg, 0.78 mmol).
  • a white solid compound 19 (160 mg, yield 77.5%) was prepared from compound 1-5-19 (370 mg, 0.34 mmol) and trifluoroacetic acid (2.4 mL, 34 mmol).
  • a white solid compound 1-3-20 (347 mg, 0.59 mmol) and I-1 (234 mg, 0.56 mmol).
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 8.93 (s, 1H), 8.08 (s, 1H), 7.59 - 7.01 (m, 35H), 6.96 (s, 1H), 6.71 (s, 1H), 6.58 (s, 1H), 5.66 - 5.57 (m, 1H), 4.79 - 4.63 (m, 1H), 4.62 - 4.45 (m, 1H).
  • a white solid compound 1-5-20 (200 mg, yield 47.8%) was prepared from compound 1-3-20 (347 mg, 0.37 mmol) and 1-4 (117 mg, 0.56 mmol).
  • a white solid compound 20 (80 mg, yield 81.6%) was prepared from compound 1-5-20 (200 mg, 0.18 mmol) and trifluoroacetic acid (0.7 mL, 8.89mmol).
  • a pale yellow solid compound I-3-21 (300 mg, yield 65.2%) was prepared from compound a-5-1 (280 mg, 0.54 mmol) and 1-1-1 (190 mg, 0.54 mmol).
  • a white solid compound 1-5-21 (274 mg, yield: 80.7%) was prepared from compound 1-3-21 (300 mg, 0.35 mmol) and 1-4 (111 mg, 0.53 mmol).
  • a white solid compound 21 (82 mg, yield 47.9%) was prepared from compound 1-5-21 (270 mg, 0.28 mmol) and trifluoroacetic acid (1.0 mL, 14.0 mmol).
  • a pale yellow solid compound 1-3-22 (348 mg, yield 66.3%) was prepared from compound a-5-1 (340 mg, 0.65 mmol) and 1-1-2 (191 mg, 0.62 mmol).
  • a white solid compound 1-5-22 (333 mg, yield 81.6%) was prepared from compound 1-3-22 (330 mg, 0.41 mmol) and 1-4 (112 mg, 0.53 mmol).
  • a white solid compound 22 (140 mg, yield 77.2%) was prepared from compound 1-5-22 (320 mg, 0.32 mmol) and trifluoroacetic acid (2.3 mL, 32.0 mmol).
  • a pale yellow solid compound 1-3-23 (188 mg, yield 32.4%) was prepared from compound a-5-1 (387 mg, 0.75 mmol) and 1-1-3 (136 mg, 0.50 mmol).
  • a white solid compound 1-5-23 (200 mg, yield 87.7%) was prepared from compound 1-3-23 (183 mg, 0.24 mmol) and 1-4 (74.5 mg, 0.36 mmol).
  • a white solid compound 23 (89 mg, yield: 80.1%) was prepared from compound 1-5-23 (200 mg, 0.21 mmol) and trifluoroacetic acid (1. 5 mL, 21.0 mmol).
  • a white solid compound 1-5-24 (368 mg, yield: 86.1%) was prepared from compound 1-3-24 (340 mg, 0.46 mmol) and 1-4 (144 mg, 0.69 mmol).
  • a white solid compound 24 (132 mg, yield 58.2%) was prepared from compound 1-5-24 (357 mg, 0.38 mmol) and trifluoroacetic acid (2.8 mL, 38.0 mmol).
  • a white solid compound 1-5-25 (385 mg, yield 86.6%) was prepared from compound 1-3-25 (350 mg, 0.49 mmol) and 1-4 (156 mg, 0.74 mmol).
  • a white solid compound 25 (100 mg, yield 67.7%) was prepared from compound 1-5-25 (237 mg, 0.26 mmol) and trifluoroacetic acid (1.9 mL, 26.3 mmol).
  • a pale yellow solid compound 1-3-26 (520 mg, yield 83.7%) was prepared from compound b-6 (400 mg, 0.77 mmol) and 1-1-2 (224 mg, 0.73 mmol).
  • a white solid compound 1-5-26 (440 mg, yield 68.3%) was prepared from compound 1-3-26 (520 mg, 0.64 mmol) and 1-4 (203 mg, 0.97 mmol).
  • a white solid compound 26 (106 mg, yield 71.9%) was prepared from compound 1-5-26 (260 mg, 0.26 mmol) and trifluoroacetic acid (2.0 mL, 26 mmol).
  • a pale yellow solid compound 1-3-27 (390 mg, yield 49.4%) was prepared from compound b-6 (527 mg, 1.02 mmol) and 1-1-3 (250 mg, 0.91 mmol).
  • a white solid compound 1-5-27 (300 mg, yield 77.6%) was prepared from compound 1-3-27 (310 mg, 0.4 mmol) and 1-4 (126 mg, 0.6 mmol).
  • a white solid compound 27 (116 mg, yield: 65.9%) was prepared from compound 1-5-27 (320 mg, 0.33 mmol) and trifluoroacetic acid (2.4 mL, 33.0 mmol).
  • Example 28 Preparation of (3S)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((S)-1-(1,5-dihydroxy-4-oxo-1,4-Dihydropyridin-2-yl)-2-methylisopropyloxy)imine)acetamido)-2,2-dim ethyl-4-oxoazetidine-1-hydrogen sulfate (Compound 28)
  • a pale yellow solid compound 1-3-28 (683mg, yield: 82.5%) was prepared from compound g-10-1 (480 mg, 0.88 mmol) and 1-1 (327 mg, 0.79 mmol).
  • a white solid compound 28 (135 mg, yield 71.9%) was prepared from compound 1-5-28 (380 mg, 0.34 mmol) and trifluoroacetic acid (2.4 mL, 33.5 mmol).
  • a pale yellow solid compound 1-3-29 (595 mg, yield 81.9%) was prepared from compound g-10-1 (475 mg, 0.87 mmol) and 1-1-2 (239 mg, 0.78 mmol).
  • a white solid compound 1-5-29 (640 mg, yield 89.8%) was prepared from compound 1-3-29 (580 mg, 0.69 mmol) and 1-4 (219 mg, 1.04 mmol).
  • a white solid compound 29 (145 mg, yield 81.2%) was prepared from compound 1-5-29 (310 mg, 0.30 mmol) and trifluoroacetic acid (2.1 mL, 30mmol).
  • a pale yellow solid compound 1-3-30 (560 mg, yield 84.9%) was prepared from compound g-10-1 (450 mg, 0.82 mmol) and 1-1-3 (224 mg, 0.82 mmol).
  • a white solid compound 1-5-30 (545 mg, yield 86.3%) was prepared from compound 1-3-30 (510 mg, 0.64 mmol) and 1-4 (200 mg, 0.95 mmol).
  • a white solid compound 30 (140 mg, yield: 83.1%) was prepared from compound 1-5-30 (298 mg, 0.30 mmol) and trifluoroacetic acid (2.1 mL, 30 mmol).
  • a pale yellow solid compound I-3-31 (500 mg, yield 72.5%) was prepared from compound g-9-1 (400 mg, 0.73 mmol) and 1-1 (242 mg, 0.59 mmol).
  • a white solid compound 1-5-31 (520 mg, yield 89.9%) was prepared from compound 1-3-31 (480 mg, 0.51 mmol) and 1-4 (160 mg, 0.76 mmol).
  • a white solid compound 31 (110 mg, yield 60.2%) was prepared from compound 1-5-31 (370 mg, 0.33 mmol) and trifluoroacetic acid (2.35 mL, 32.6 mmol).
  • a pale yellow solid compound 1-3-32 (510 mg, yield 80.6%) was prepared from compound g-9-1 (415 mg, 0.76 mmol) and 1-1-2 (209 mg, 0.68 mmol).
  • a white solid compound 1-5-32 (567 mg, yield: 90.1%) was prepared from compound 1-3-32 (510 mg, 0.61 mmol) and 1-4 (192 mg, 0.92 mmol).
  • a white solid compound 32 (130 mg, yield: 68.3%) was prepared from compound 1-5-32 (330 mg, 0.32 mmol) and trifluoroacetic acid (2.4 mL, 32 mmol).
  • a pale yellow solid compound 1-3-33 (533 mg, yield 75.8%) was prepared from compound g-9-1 (480 mg, 0.88 mmol) and 1-1-3 (240 mg, 0.88 mmol).
  • a white solid compound 1-5-33 (520 mg, yield 81.8%) was prepared from compound 1-3-33 (513 mg, 0.64 mmol) and 1-4 (202 mg, 0.96 mmol).
  • a white solid compound 33 (100 mg, yield: 67.9%) was prepared from compound 1-5-33 (260 mg, 0.26 mmol) and trifluoroacetic acid (1.8 mL, 26.2 mmol).
  • a white solid compound 1-3-34 (371 mg, yield 76.0%) was prepared from compound g-17-1 (287 mg, 0.51 mmol) and 1-1 (200 mg, 0.48 mmol).
  • a pale yellow solid compound 1-5-34 (335 mg, yield: 83.3%) was prepared from compound 1-3-34 (336 mg, 0.35 mmol) and 1-4 (110 mg, 0.52 mmol).
  • a white solid compound 34 (118 mg, yield: 87.2%) was prepared from compound 1-5-34 (270 mg, 0.23 mmol) and trifluoroacetic acid (1.7 mL, 23 mmol).
  • a yellow solid compound 1-3-35 (522 mg, yield: 85.3%) was prepared from compound g-16-1 (360 mg, 0.64 mmol) and 1-1 (264 mg, 0.64 mmol).
  • a white solid compound 35 (109 mg, yield: 71.4%) was prepared from compound 1-5-35 (304 mg, 0.26 mmol) and trifluoroacetic acid (1. 9 mL, 26 mmol).
  • Example 36 Preparation of (3S)-3-((Z)-2-(2-aminothiazol-4-yl)-2-((1-(1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)methylisopropyloxy)imine)acetamido)-2,2-dimeth yl-4-oxoazetidine-1-sodium sulfate (Compound 36)
  • Test Example 1 Experiments for assaying the in vitro activity of preferred compounds against multidrug-resistant negative bacteria
  • Table 1 Clinical isolated strains selected for in vitro antibacterial activity screening Name of the Strain Number Escherichia coli (ESBLs) 4 Multi-drug resistant Klebsiella pneumoniae (KPC2) 4 Multidrug-resistant Acinetobacter baumannii (integron I, OXA23) 4 Multidrug-resistant Pseudomonas aeruginosa (integrator I, IMP4) 4
  • Escherichia coli ATCC352128 purchased from National Center of Clinical Laboratory.
  • each test sample solution at different concentrations was separately aspirated onto a 96-well sterile polystyrene plate.
  • Drug solutions were added to the 1st to 10th well with the final concentrations of 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, and 0.03 mg/L in each well, respectively.
  • the 11th well, as a blank control was not added with drugs and bacteria.
  • the 12th well, as a bacterial growth control was added with bacteria but no drug.
  • test bacterial liquid was adjusted to a bacterial suspension of 0.5 Mcfarland standard with physiological saline, and diluted with MH broth at 1:100, and then added to the drug solution so that a final concentration of the bacterial liquid was approximately 10 4 CFU/ml; 100 ⁇ l of the bacterial liquid was further added to each of the above wells (the total volume in each well is 200 ⁇ l), which was sealed and placed in a 35-37 °C incubator for 18-20 h for testing the result.
  • the OD 600 value was measured by a microplate reader, Minimal Inhibitory Concentration (MIC) of a drug is the lowest concentration of the drug which prevents growth of bacteria in the wells.
  • MIC Minimal Inhibitory Concentration
  • the optimum concentration of 2,2'-bipyridine (BPL) in the medium was determined to be 16 mg/L in the preparation of iron-deficient environment; such concentration (the MH medium containing 16 mg/L 2,2'-bipyridine (BPL)) did not affect the growth of each test bacteria.
  • BPL was added to the normal MH medium to obtain a final concentration of 16 mg/L; According to the method in Section 1.2.1, 100 ⁇ l of each test sample solution at different concentrations was aspirated to the 1st to 10th well in a 96-well sterile polystyrene plate to obtain the final drug concentrations of 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, and 0.03 mg/L, respectively.
  • test bacterial liquid 100 ⁇ l of the test bacterial liquid was added to each well (200 ⁇ l per well), and the final concentration of the bacterial liquid was approximately 10 4 CFU/ml. After sealing, it was placed in a 35-37 °C incubator for 18-20 hours for testing the result.
  • the OD 600 value was measured by a microplate reader, Minimal Inhibitory Concentration (MIC) of a drug is the lowest concentration of the drug which prevents growth of bacteria in the wells.
  • MIC Minimal Inhibitory Concentration
  • BAL30072 As the positive control groups, BAL30072, aztreonam, meropenem and ceftizoxime sodium were used.
  • aztreonam is a marketed drug of monocyclic ⁇ -lactams, which is only effective against Gram-negative bacteria
  • meropenem is a marketed drug of carbapenems
  • ceftizoxime sodium is a marketed drug of the third-generation cephalosporins
  • BAL30072 is a monocyclic ⁇ -lactam-iron carrier conjugate in clinical phase I.
  • the compounds of the present invention have potent anti-negative bacteria activity in vitro, which is significantly better than the activity of the positive control drugs BAL-30072, aztreonam, meropenem and ceftizoxime sodium. More importantly, the antibacterial spectrum of the compounds of the invention covers the four most important multi-drug resistant Gram-negative bacteria, i.e., Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.
  • the compounds of the present invention also have potent antibacterial activity against multidrug-resistant Klebsiella pneumoniae (KPC2) which is resistant to BAL-30072, aztreonam, meropenem, and ceftizoxime sodium.
  • KPC2 multidrug-resistant Klebsiella pneumoniae
  • the compounds of the present invention have significantly more potent antibacterial activity against Escherichia coli and Klebsiella pneumoniae, for example:
  • the Example compound 12 is 4-32 times more effective than BAL30072 in its inhibitory activity against Escherichia coli; and 64-128 times more effective than BAL30072 in its inhibitory activity against Klebsiella pneumoniae.
  • Example compound 16 is 2-8 times more effective than BAL30072 in its inhibitory activity against Escherichia coli; and 64-128 times more effective than BAL30072 in its inhibitory activity against Klebsiella pneumoniae.
  • the Example compound 22 is 4-16 times more effective than BAL30072 in its inhibitory activity against Escherichia coli; and 64 times more effective than BAL30072 in its inhibitory activity against Klebsiella pneumoniae.
  • Table 3 Antibacterial activity MIC of the compounds of the present invention under iron-deficient MH medium condition (unit: mg/L) Compound Escherichia coli ATCC 35218 Escherichia coli (4 strains) Klebsiella pneumoniae (4 strains) Acinetobacter baumannii (4 strains) Pseudomonas aeruginosa (4 strains) Compound 12 ⁇ 0.03 0.03-0.25 0.25-0.5 0.5-1 0.25-1 Compound 16 ⁇ 0.03 0.06-0.25 0.5-1 0.5-1 0.125-1 Compound 22 ⁇ 0.03 0.06-0.25 1 1 0.5-1 Compound 24 ⁇ 0.03 0.06-0.25 0.125-0.5 1-2 0.25-2 Compound 26 ⁇ 0.03 0.03-0.25 0.5-4 0.5-1 0.25-1 Com
  • the 2,2'-bipyridine is used to simulate the real environment in the body by chelating the iron in the normal medium to create an iron-deficient environment, and bacteria is stimulated to secret a large amount of iron carrier to compete with 2,2'-bipyridine for iron in the substrate, which stimulates a unique iron-producing pathway of bacteria, facilitating the antibacterial action of iron-antibiotic conjugates.
  • free iron is bonded to transferrin, causing that a very low concentration of free iron could be used by bacteria, while iron-deficient medium supplemented with 2,2'-bipyridine exactly simulates the low iron environment in the body, thus, iron-deficient medium condition is considered to better reflect the antibacterial effects of the compounds.
  • Table 3 shows that the in vitro anti-negative bacteria activity of the compounds of the present invention is further improved under iron-deficient condition as compared with normal condition, demonstrating the mechanism by which the iron carrier-antibiotic conjugate exerts an antibacterial effect.
  • the compounds of the present invention have significantly more superior effect against the four most important multidrug-resistant Gram-negative bacteria, i.e., Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa.
  • the Example compound 12 is 128-256 times more effective than BAL30072 in the inhibitory activity against Klebsiella pneumonia.
  • the Example compound 16 is 64-128 times more effective than BAL30072 in the inhibitory activity against Klebsiella pneumonia.
  • the Example compound 22 is 64 times more effective than BAL30072 in the inhibitory activity against Klebsiella pneumonia.
  • the Example compound 24 is 128-512 times more effective than BAL30072 in the inhibitory activity against Klebsiella pneumonia.
  • the Example compound 26 is 16-128 times more effective than BAL30072 in the inhibitory activity against Klebsiella pneumonia.
  • the Example compound 28 is 64 times more effective than BAL30072 in the inhibitory activity against Klebsiella pneumonia.
  • the Example compound 29 is 128-256 times more effective than BAL30072 in the inhibitory activity against Klebsiella pneumonia.
  • the compounds of the present invention have significantly more superior antibacterial activity in vitro against Gram-negative bacteria (including multidrug-resistant negative bacteria), thus they have more potent antibacterial activity and broader antibacterial spectrum.
  • the compounds of the present invention also have potent antibacterial activity against multi-drug resistant Klebsiella pneumoniae (KPC2) which is resistant to BAL-30072, aztreonam, meropenem, and ceftizoxime sodium.
  • KPC2 multi-drug resistant Klebsiella pneumoniae
  • Test drug BAL30072, Example Compound 12.
  • Test animals 6 SD rats, male, weight: 200-220 g.
  • Intravenous administration 2 min, 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h and 3 h after administration.
  • 0.3 ml of venous blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized tube, centrifuged at 11,000 rpm for 5 min, then the plasma was separated and stored in a refrigerator at -20 °C. All of the rats were fed 2 hours after administration.
  • the concentration of BAL30072 and Example Compound 12 in plasma of the rats was determined by LC/MS/MS method.
  • the disadvantage of the compounds of the present invention is that the half-life is too short, which will be disadvantageous for the drug's efficacy, thus intravenous drip administration is generally recommended.
  • the data in Table 4 shows that the area under the curve AUC 0-t of the compounds of the present invention is slightly better than that of BAL30072, and the half-life, T 1/2 0.45 ⁇ 0.11 h, is significantly longer than that of BAL30072.
  • the compounds of the present invention have superior metabolic properties than BAL30072, and each metabolic parameter thereof is ideal.
  • Test Example 3 Test for the in vivo efficacy of the compounds of the present invention against Gram-negative bacteria in mice
  • Test strains Clinically isolated pathogenic Escherichia coli ECO-14-4 (ESBLs), supplied by Sichuan Primed Shines Bio-tech Co., Ltd.
  • Test animals Kunming mice, age: 4 to 5 weeks, weight: 18 to 22 g, half male, half female, SPF grade.
  • mice were randomly divided into several groups, 5 mice for each group, half male and half female, and 5 doses for each test drug: 1.25, 2.5, 5, 10 and 20 mg/kg.
  • the mice were intraperitoneally injected with 0.5 mL of 5.0 ⁇ 10 4 CFU/mL bacterial suspension for each mouse, and subcutaneously injected with the drug at the designed dose 0.5 h and 4 h after infection.
  • the subcutaneous injection volume was 0.2 ml/20 g mouse weight; the number of deaths in mice was observed and recorded for 7 consecutive days. According to the number of deaths in mice, the half effective dose ED 50 was calculated according to the Bliss method using the DAS 1.0 software, edited by Sun Ruiyuan et al.
  • Test Example 4 Test for in vivo efficacy of the compounds of the present invention against multidrug-resistant Gram-negative bacteria in mice
  • Test strains clinically isolated pathogenic multidrug-resistant Klebsiella pneumoniae KR15-4 (KPC2), provided by Sichuan Primed Shines Bio-tech Co., Ltd.
  • Test animals Kunming mice, age: 4 to 5 weeks, weight: 18 to 22 g, half male, half female, SPF grade.
  • mice were randomly divided into several groups, 5 mice for each group, half male and half female, and 4 doses for each test drug: 12.5, 25, 50 and 100 mg/kg.
  • the mice were intraperitoneally injected with 0.5 mL of 3.0 ⁇ 10 6 CFU/mL bacterial suspension for each mouse, and subcutaneously injected with the drug at the designed dose 0.5 h and 4 h after infection.
  • the subcutaneous injection volume was 0.2 ml/20 g mouse weight; the number of deaths in mice was observed and recorded for 7 consecutive days. According to the number of deaths in mice, the half effective dose ED 50 was calculated according to the Bliss method using the DAS 1.0 software, edited by Sun Ruiyuan et al.
  • compound 12 of the present invention exhibits potent protective effect in vivo for the mice model systemically infected with clinically isolated pathogenic multidrug-resistant Klebsiella pneumoniae KR15-4 (KPC2), and half effective dose ED 50 via subcutaneous injection was 10.20 mg/kg, while the marketed drugs meropenem and aztreonam and the control compound BAL30072 show no in vivo protective effects in the dose range, and their ED 50 values were greater than 100 mg/kg, indicating that compound 12 of the present invention has a very good therapeutic effect on the mice systemically infected with clinically isolated pathogenic multidrug-resistant Klebsiella pneumoniae KR15-4 (KPC2), thus the effect thereof is significantly better than those of the existing drugs, meropenem and aztreonam and the control compound BAL30072, it is further proved that compound 12 of the invention has a significant advantage in the treatment of infection caused by multidrug-resistant Gram-negative bacteria.
  • the compounds of the present invention have a novel chemical structure, and their activities against Gram-negative bacteria in vivo and in vitro are significantly better than those of the drugs aztreonam, meropenem and ceftizoxime sodium, and they also show good antibacterial activity against the meropenem-resistant bacteria, meanwhile, those compounds also have ideal pharmacokinetic properties. Therefore, the compounds of the present invention can be used as a medicament for treating infectious diseases caused by Gram-negative bacteria, particularly infectious diseases caused by drug-resistant Gram-negative bacteria.

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Claims (11)

  1. Monocyclisches β-Lactam-Siderophor-Konjugat, repräsentiert durch die Formel (I), ein optisches Isomer davon oder ein pharmazeutisch akzeptables Salz davon:
    Figure imgb0103
     wobei
    X = CY oder N, wobei Y H oder ein Halogen ist;
    R das folgende ist:
    (1) eine Carboxylgruppe, -COOR1 oder -CONR2R3;
    (2) eine unsubstituierte lineare C1-6 Alkylgruppe, eine unsubstituierte verzweigte C3-6 Alkylgruppe, eine C3-6 Cycloalkylgruppe oder eine unsubstituierte C2-7 Alkenylgruppe;
    (3) eine substituierte lineare C1-4 Alkylgruppe oder eine verzweigte C3-6 Alkylgruppe, wobei der Substituent eine Hydroxylgruppe, eine Aminogruppe, eine Cyanogruppe, -OR1-SR1, -S(O2)R1, -NR2R3 und ein Halogen ist;
    (4) eine substituierte oder unsubstituierte Phenylgruppe, wobei der Substituent in der substituierten Phenylgruppe 1 bis 3 Substituenten ist, die unabhängig voneinander aus der Gruppe ausgewählt sind, bestehend aus einer Hydroxylgruppe, einer Cyanogruppe, -R1, -OR1, -NR2R3 und einem Halogen; oder
    (5) eine substituierte oder unsubstituierte, 5- oder 6-gliedrige Heteroarylring-Gruppe, die 1 bis 4 Heteroatome aufweist, die unabhängig voneinander aus der Gruppe ausgewählt sind, bestehend aus N, S und O, wobei der Substituent in der 5- oder 6-gliedrigen Heteroarylring-Gruppe unabhängig voneinander ausgewählt ist aus der Gruppe, bestehend aus einer Hydroxylgruppe, einer Cyanogruppe, -R1, -OR1, -NR2R3 und einem Halogen;
    R1 eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe ist;
    R2 und R3 jeweils unabhängig voneinander ein Wasserstoff, eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe sind;
    das Halogen F, Cl, Br oder I ist; vorzugsweise F, Cl oder Br ist;
    eine Stereokonfiguration des alpha-Kohlenstoffs von dem S-Typ oder dem R-Typ oder dem (R, S)-Typ sein kann.
  2. Monocyclisches β-Lactam-Siderophor-Konjugat, optisches Isomer davon oder pharmazeutisch akzeptables Salz davon nach Anspruch 1, wobei Y H, Cl oder Br ist.
  3. Monocyclisches β-Lactam-Siderophor-Konjugat, optisches Isomer davon oder pharmazeutisch akzeptables Salz davon nach Anspruch 1, wobei, wenn R eine substituierte lineare C1-4 Alkylgruppe oder eine verzweigte C3-6 Alkylgruppe ist, der Substituent eine Hydroxylgruppe, -OR1, -SR1, -S(O2)R1 ist.
  4. Monocyclisches β-Lactam-Siderophor-Konjugat, optisches Isomer davon oder pharmazeutisch akzeptables Salz davon nach Anspruch 1, wobei R ausgewählt ist aus der Gruppe, bestehend aus einer Methylgruppe, einer Ethylgruppe, einer Propylgruppe, einer Butylgruppe, einer Isopropylgruppe, einer Isobutylgruppe, einer Cyclopropylgruppe und einer Vinylgruppe; einer monosubstituierten linearen C1-4 Alkylgruppe und einer verzweigten C3-6 Alkylgruppe, wobei der Substituent ausgewählt ist aus der Gruppe, bestehend aus einer Hydroxylgruppe, -OR1, -SR1 und -S(O2)R1; einer Phenylgruppe; einer substituierten oder unsubstituierten, 5- oder 6-gliedrigen Heteroarylring-Gruppe, die 1 bis 2 Heteroatome aufweist, die unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus N, S und O, wobei der Substituent in der 5- oder 6-gliedrigen Heteroarylring-Gruppe unabhängig voneinander ausgewählt ist aus der Gruppe, bestehend aus einer Hydroxylgruppe, einer Cyanogruppe, -R1, -OR1, -NR2R3 und einem Halogen.
  5. Monocyclische β-Lactam-Siderophor-Konjugat, optisches Isomer davon oder pharmazeutisch akzeptables Salz davon nach einem der Ansprüche 1 bis 4, wobei R1 eine Methylgruppe, eine Ethylgruppe, eine Propylgruppe, eine Isopropylgruppe, eine n-Butylgruppe, eine Isobutylgruppe, eine sec-Butylgruppe, eine tert-Butylgruppe oder eine Cyclopropylgruppe ist; R2 und R3 jeweils unabhängig voneinander ein Wasserstoff, eine Methylgruppe, eine Ethylgruppe, eine Propylgruppe, eine Isopropylgruppe, eine n-Butylgruppe, eine Isobutylgruppe, eine sec-Butylgruppe, eine tert-Butylgruppe oder eine Cyclopropylgruppe sind.
  6. Monocyclische β-Lactam-Siderophor-Konjugat, optisches Isomer davon oder pharmazeutisch akzeptables Salz davon nach einem der Ansprüche 1 bis 4, wobei R1 eine Methylgruppe, eine Ethylgruppe, eine Propylgruppe, eine Isopropylgruppe ist; R2 und R3 jeweils unabhängig voneinander ein Wasserstoff, eine Methylgruppe, eine Ethylgruppe, eine Propylgruppe, eine Isopropylgruppe sind.
  7. Monocyclische β-Lactam-Siderophor-Konjugat, optisches Isomer davon oder pharmazeutisch akzeptables Salz davon nach einem der Ansprüche 1 bis 4, wobei die repräsentative Verbindung der Formel (I) eine der folgenden Verbindungen ist:
    Figure imgb0104
    Figure imgb0105
    Figure imgb0106
    Figure imgb0107
  8. Pharmazeutische Zusammensetzung, umfassend das monocyclische β-Lactam-Siderophor-Konjugat, das optische Isomer davon oder das pharmazeutisch akzeptable Salz davon nach einem der Ansprüche 1 bis 7 als einen wirksamen Bestanteil, und einen pharmazeutisch akzeptablen Hilfsstoff.
  9. Verwendung von dem monocyclischen β-Lactam-Siderophor-Konjugat, dem optischen Isomer davon oder dem pharmazeutisch akzeptablen Salz davon nach einem der Ansprüche 1 bis 7 zum Herstellen eines Medikaments zur Behandlung einer Infektionskrankheit, die durch Bakterien verursacht ist, insbesondere umfassend die Infektionskrankheiten, die durch sensitiven und resistenten Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli und Klebsiella pneumonie verursacht werden.
  10. Verfahren zum Herstellen von dem monocyclischen β-Lactam-Siderophor-Konjugat, dem optischen Isomer davon oder dem pharmazeutisch akzeptablen Salz davon nach einem der Ansprüche 1 bis 7, umfassend die Schritte, die in dem folgenden Reaktionsschema (1) gezeigt sind:
    Figure imgb0108
     wobei in dem oben genannten Reaktionsschema (1) X und R wie in Anspruch 1 definiert sind; Ra eine Aminoschutzgruppe ist; R1
    Figure imgb0109
     ist, wobei Rb eine Hydroxylschutzgruppe ist;
    (a) Zur-Reaktion-Bringen von der Verbindung I-1 mit der Verbindung I-2 in einem gemischten Lösungsmittel aus einem polaren protischen Lösungsmittel und einem unpolaren Lösungsmittel bei Raumtemperatur für 2 bis 6 Stunden, um eine Verbindung I-3 zu erhalten;
    (b) Zur-Reaktion-Bringen von der Verbindung I-3 mit der Verbindung I-4 unter einer Bedingung eines Kondensationsmittels und einer organischen oder anorganischen Base in einem polaren aprotischen Lösungsmittel als ein Lösungsmittel bei Raumtemperatur für 4 bis 8 Stunden, um eine Verbindung I-5 zu erhalten;
    (c) Entfernen von der Schutzgruppe der Verbindung I-5 mittels einer Säure in einem unpolaren Lösungsmittel in Gegenwart eines positiven Ionenfallenmittels, um eine Verbindung I zu erhalten.
  11. Verfahren nach Anspruch 10, wobei das Verfahren zum Synthetisieren des Schlüsselzwischenprodukts I-2 aus einem der folgenden Verfahren ausgewählt sein kann:
    Verfahren I:
    Figure imgb0110
     wobei R eine lineare C1-4 Alkylgruppe oder eine C1-4 Alkenylgruppe oder eine C3-4 Cycloalkylgruppe ist;
    (a) Oxidieren von der Verbindung a-1 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel für 4 bis 8 Stunden, um eine Verbindung a-2 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel eine Mischung aus Schwefeltrioxid-Pyridin und Dimethylsulfoxid oder eine Mischung aus Oxalylchlorid und Dimethylsulfoxid ist;
    (b) Zur-Reaktion-Bringen von der Verbindung a-2 mit einem Metall-Grignard-Reagens RMgX in einem unpolaren Lösungsmittel bei einer niedrigen Temperatur von -10 bis -20 °C für 4 bis 6 Stunden, um eine Verbindung a-3 zu erhalten, wobei das Metall-Grignard-Reagens RMgBr oder RMgCl ist und das unpolare Lösungsmittel Tetrahydrofuran ist;
    (c) Unterziehen von der Verbindung a-3 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung a-4 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (d) Unterziehen von der Verbindung a-4 mit Hydrazinhydrat einer Hydrazinolyse oder der Verbindung a-4 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung a-5 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist;
    Verfahren II:
    Figure imgb0111
     wobei R eine lineare C1-4 Alkylgruppe oder eine C1-4 Alkenylgruppe oder eine C3-4 Cycloalkylgruppe ist;
    (a) Oxidieren von der Verbindung a-2 mit einem Oxidationsmittel in einem gemischten Lösungsmittel aus Wasser und einem polaren aprotischen Lösungsmittel, um eine Verbindung b-1 zu erhalten, wobei das polare aprotische Lösungsmittel Acetonitril, Aceton oder 1,4-Dioxan ist und das Oxidationsmittel Natriumchlorit ist;
    (b) Zur-Reaktion-Bringen von der Verbindung b-1 mit N-Methyl-N-methoxyaminhydrochlorid unter der Bedingung eines Kondensationsmittels und einer organischen oder anorganischen Base in einem polaren aprotischen Lösungsmittel als ein Lösungsmittel bei Raumtemperatur für 4 bis 8 Stunden, um eine Verbindung b-2 zu erhalten, wobei das Kondensationsmittel das folgende ist: eine Mischung aus 2-(7-Azabenzotriazolyl)-N,N,N',N'-tetramethyluroniumhexafluorophosphat (HATU) oder 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidhydrochlorid (EDCI) und 1-Hydroxybenzotriazol (HOBT), die organische Base das folgende ist: Triethylamin oder Diisopropylethylamin, die anorganische Base Natriumhydrogencarbonat, Natriumcarbonat oder Kaliumhydrogencarbonat ist und das polare aprotische Lösungsmittel das folgende ist: Dimethylsulfoxid oder N,N-Dimethylformamid;
    (c) Zur-Reaktion-Bringen von der Verbindung b-2 mit einem Metall-Grignard-Reagens RMgX in einem unpolaren Lösungsmittel bei einer niedrigen Temperatur von -10 bis -20 °C für 4 bis 6 Stunden, um eine Verbindung b-3 zu erhalten, wobei das Metall-Grignard-Reagens RMgBr oder RMgCl ist und das unpolare Lösungsmittel Tetrahydrofuran oder Diethylcther ist;
    (d) Zur-Reaktion-Bringen von der Verbindung b-3 durch die Wirkung eines Übergangsmetallkatalysators, eines Liganden und einer Wasserstoffquelle in einem polaren Lösungsmittel unter Ar-Schutz, um eine Verbindung b-4 oder b-5 zu erhalten, wobei der Übergangsmetallkatalysator ein Dichlorbis(4-methylisopropylphenyl)ruthenium(II)-Dimer oder ein Dichlor(pentamethylcyclopentadienyl)rhodium(III)-Dimer ist, der Ligand (1R,2R)-(-)-N-(p-Methylbenzolsulfonyl)-1,2-diphenylethylendiamin oder (1S,2S)-(-)-N-(p-Methylbenzolsulfonyl)-1,2-diphenylethylendiamin ist, die Wasserstoffquelle Natriumformiat oder Ammoniumformiat ist und das polare Lösungsmittel N,N-Dimethylformamid ist;
    (e) Unterziehen von der Verbindung b-4 oder b-5 dem Verfahren, das in dem Verfahren I beschrieben ist, um eine Verbindung b-6 oder b-7 zu erhalten;
    Verfahren III:
    Figure imgb0112
     wobei R eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6-Cycloalkylgruppe ist; und R1 und R2 jeweils unabhängig voneinander das folgende sind: ein Wasserstoff; oder eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe;
    (a) Unterziehen von der Verbindung c-1 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung c-2 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (b) Unterziehen von der Verbindung c-2 mit Hydrazinhydrat einer Hydrazinolyse oder der Verbindung c-2 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung c-3 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist;
    (c) Zur-Reaktion-Bringen von der Verbindung c-1 in einem gemischten Lösungsmittel aus einem polaren und unpolaren Lösungsmittel in Gegenwart einer anorganischen Base bei 0 °C bis Raumtemperatur, um eine Verbindung c-4 zu erhalten, wobei die anorganische Base Natriumhydroxid oder Lithiumhydroxid, das polare Lösungsmittel Wasser oder Methanol und das unpolare Lösungsmittel Tetrahydrofuran ist;
    (d) Zur-Reaktion-Bringen von der Verbindung c-4 mit Diphenyldiazomethan in einem gemischten Lösungsmittel aus einem polaren und unpolaren Lösungsmittel, um eine Verbindung c-5 zu erhalten, wobei das polare Lösungsmittel Methanol oder Ethanol ist und das unpolare Lösungsmittel Dichlormethan, Ethylacetat oder Tetrahydrofuran ist;
    (e) Unterziehen von der Verbindung c-5 den oben genannten Schritten a und b, um eine Verbindung c-6 zu erhalten;
    (f) Unterziehen von der Verbindung c-1 mit HNR1R2 einer Aminolyse in einem polaren protischen Lösungsmittel oder einem unpolaren Lösungsmittel, um eine Verbindung c-7 zu erhalten, wobei das polare protische Lösungsmittel ein Methanol ist und das unpolare Lösungsmittel Tetrahydrofuran ist;
    (g) Zur-Reaktion-Bringen von der Verbindung c-4 mit dem Amin HNR1R2 in einem polaren Lösungsmittel in Gegenwart eines Kondensationsmittels und einer organischen Base bei Raumtemperatur, um eine Verbindung c-7 zu erhalten, wobei das Kondensationsmittel 2-(7-Azabenzotriazolyl)-N,N,N',N'-tetramethyluroniumhexafluorophosphat (HATU) oder 1-Hydroxybenzotriazol (HOBT) ist, die organische Base Triethylamin oder Diisopropylethylamin ist und das polare Lösungsmittel Dichlormethan ist;
    (h) Unterziehen von der Verbindung c-7 den oben genannten Schritten a und b, um eine Verbindung c-8 zu erhalten;
    wobei das synthetische Verfahren von dem Ausgangsmaterial c-1 in dem oben genannten Reaktionsschema wie folgt ist:
    Figure imgb0113
     wobei R eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe ist;
    (a) Oxidieren von der Verbindung c-9 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel für 4 bis 8 Stunden, um eine Verbindung c-10 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel eine Mischung aus Schwefeltrioxid-Pyridin und Dimethylsulfoxid oder eine Mischung aus Oxalylchlorid und Dimethylsulfoxid ist;
    (b) Zur-Reaktion-Bringen von der Verbindung c-10 mit Natriumcyanid in einem gemischten Lösungsmittel aus Wasser und einem unpolaren Lösungsmittel, um eine Verbindung c-11 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (c) Zur-Reaktion-Bringen von der Verbindung c-11 mit Salzsäure in einem polaren protischen Lösungsmittel, um eine Verbindung c-12 zu erhalten, wobei das polare protische Lösungsmittel ein Alkohol ROH ist;
    (d) Oxidieren von der Verbindung c-12 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel, um eine Verbindung c-13 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist, das Oxidationsmittel m-Chlorperoxybenzoesäure (mCPBA) oder Wasserstoffperoxid ist;
    (e) Unterziehen von der Benzyl-Schutzgruppe der Verbindung c-13 einer Entschützung in einem unpolaren Lösungsmittel unter der Wirkung einer Lewis-Säure, um eine Verbindung c-14 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist, die Lewis-Säure Bortrichlorid oder Bortribromid ist;
    (f) Zur-Reaktion-Bringen von der Verbindung c-14 mit Diphenyldiazomethan in einem gemischten Lösungsmittel aus einem polaren und unpolaren Lösungsmittel, um eine Verbindung c-1 zu erhalten, wobei das polare Lösungsmittel Methanol oder Ethanol ist, das unpolare Lösungsmittel Dichlormethan, Ethylacetat oder Tetrahydrofuran ist;
    Verfahren IV:
    Figure imgb0114
     wobei in dem oben genannten Schema R eine Hydroxylgruppe, eine Aminogruppe, -OR1, -NR2R3 ist; -R1 eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe ist; und R2 und R3 jeweils unabhängig voneinander das folgende sind: ein Wasserstoff oder eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe;
    (a) Zur-Reaktion-Bringen von der Verbindung c-10 mit Trimethylsulfoxoniumiodid oder Trimethylsulfoxoniumiodid unter der Wirkung einer starken Lauge in einem polaren aprotischen Lösungsmittel, um eine Verbindung d-1 zu erhalten, wobei das polare aprotische Lösungsmittel Dimethylsulfoxid oder N,N-Dimethylformamid ist und die starke Lauge Natriumhydrid oder Kaliumhydrid ist;
    (b) Zur-Reaktion-Bringen von der Verbindung d-1 mit RH in einem unpolaren Lösungsmittel unter einer starken Lauge, um eine Verbindung d-2 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran ist und die starke Lauge Natriumhydrid, Natriumhydroxid oder Kaliumhydroxid ist;
    (c) Unterziehen von der Verbindung d-2 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung d-3 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (d) Oxidieren von der Verbindung d-3 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel, um eine Verbindung d-4 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel m-Chlorperoxybenzoesäure oder Wasserstoffperoxid ist;
    (e) Unterziehen von der Benzyl-Schutzgruppe der Verbindung d-4 einer Entschützung unter der Wirkung einer Lewis-Säure in einem unpolaren Lösungsmittel, um eine Verbindung d-5 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und die Lewis-Säure Bortrichlorid oder Bortribromid ist;
    (f) Zur-Reaktion-Bringen von der Verbindung d-5 mit Diphenyldiazomethan in einem gemischten Lösungsmittel aus einem polaren und unpolaren Lösungsmittel, um eine Verbindung d-6 zu erhalten, wobei das polare Lösungsmittel Methanol oder Ethanol ist und das unpolare Lösungsmittel Dichlormethan, Ethylacetat oder Tetrahydrofuran ist;
    (g) Unterziehen von der Verbindung d-6 mit Hydrazinhydrat einer Hydrazinolyse oder der Verbindung d-6 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung d-7 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist;
    Verfahren V:
    Figure imgb0115
     wobei in dem oben genannten Schema R eine Hydroxylgruppe, eine Aminogruppe, -OR1, -SR1, -NR2R3 ist; R1 eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe ist; und R2 und R3 jeweils unabhängig voneinander das folgende sind: ein Wasserstoff oder eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe;
    (a) Oxidieren von der Verbindung d-1 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel, um eine Verbindung d-8 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel m-Chlorperoxybenzoesäure oder Wasserstoffperoxid ist;
    (b) Zur-Reaktion-Bringen von der Verbindung d-8 mit RH in einem unpolaren Lösungsmittel unter einer starken Lauge, um eine Verbindung d-9 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran ist und die starke Lauge Natriumhydrid, Natriumhydroxid oder Kaliumhydroxid ist;
    (c) Unterziehen von der Benzyl-Schutzgruppe der Verbindung d-9 einer Entschützung in einem unpolaren Lösungsmittel unter der Wirkung einer Lewis-Säure, um eine Verbindung d-10 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und die Lewis-Säure Bortrichlorid oder Bortribromid ist;
    (d) Zur-Reaktion-Bringen von der Verbindung d-10 mit Diphenyldiazomethan in einem gemischten Lösungsmittel aus einem polaren und unpolaren Lösungsmittel, um eine Verbindung d-11 zu erhalten, wobei das polare Lösungsmittel Methanol oder Ethanol ist und das unpolare Lösungsmittel Dichlormethan, Ethylacetat oder Tetrahydrofuran ist;
    (e) Unterziehen von der Verbindung d-11 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung d-12 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (f) Unterziehen von der Verbindung d-12 mit Hydrazinhydrat einer Hydrazinolyse oder der Verbindung d-12 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung d-13 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist;
    Verfahren VI:
    Figure imgb0116
     wobei in dem oben genannten Schema R eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe, eine C3-6 Cycloalkylgruppe, eine substituierte oder unsubstituierte Phenylgruppe oder eine substituierte oder unsubstituierte, 5- oder 6-gliedrige Heteroarylring-Gruppe ist, die 1 bis 4 Heteroatome aufweist, die unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus N, S und O ist;
    (a) Zur-Reaktion-Bringen von der Verbindung c-10 mit einem Grignard-Reagens RMgBr oder einem Organolithium-Reagens RLi in einem unpolaren Lösungsmittel, um eine Verbindung e-1 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder Methyltetrahydrofuran ist;
    (b) Unterziehen von der Verbindung e-1 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung e-2 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (c) Oxidieren von der Verbindung e-2 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel, um eine Verbindung e-3 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel m-Chlorperoxybenzoesäure oder Wasserstoffperoxid ist;
    (d) Unterziehen von der Benzyl-Schutzgruppe der Verbindung e-3 einer Entschützung in einem unpolaren Lösungsmittel unter der Wirkung einer Lewis-Säure, um eine Verbindung e-4 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und die Lewis-Säure Bortrichlorid oder Bortribromid ist;
    (e) Zur-Reaktion-Bringen von der Verbindung e-4 mit Diphenyldiazomethan in einem gemischten Lösungsmittels aus einem polaren und unpolaren Lösungsmittel, um eine Verbindung e-5 zu erhalten, wobei das polare Lösungsmittel Methanol oder Ethanol ist und das unpolare Lösungsmittel Dichlormethan, Ethylacetat oder Tetrahydrofuran ist;
    (f) Unterziehen von der Verbindung e-5 einer Hydrazinolyse mit Hydrazinhydrat oder der Verbindung e-5 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung e-6 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist;
    Verfahren VII:
    Figure imgb0117
     wobei in dem oben genannten Schema R eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe, eine C3-6 Cycloalkylgruppe, eine substituierte oder unsubstituierte Phenylgruppe oder eine substituierte oder unsubstituierte, 5- oder 6-gliedrige Heteroarylring-Gruppe ist, die 1 bis 4 Heteroatome aufweist, die unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus N, S und O ist;
    wobei sich das synthetische Verfahren der Verbindung f-1 auf das Verfahren der Verbindung c-10 Bezug nehmen kann;
    (a) Zur-Reaktion-Bringen von der Verbindung f-1 mit einem Grignard-Reagens RMgBr oder einem Organolithium-Reagens RLi in einem unpolaren Lösungsmittel, um eine Verbindung f-2 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder Methyltetrahydrofuran ist;
    (b) Unterziehen von der Verbindung f-2 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung f-3 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (c) Oxidieren von der Verbindung f-3 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel, um eine Verbindung f-4 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel m-Chlorperoxybenzoesäure oder Wasserstoffperoxid ist;
    (d) Unterziehen von der Verbindung f-4 mit Hydrazinhydrat einer Hydrazinolyse oder der Verbindung f-4 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung f-5 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist;
    Verfahren VIII:
    Figure imgb0118
     wobei in dem oben genannten Schema R eine Hydroxylgruppe, eine Aminogruppe, -OR1, -NR2R3 ist; R1 eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe ist; und R2 und R3 jeweils unabhängig voneinander das folgende sind: ein Wasserstoff oder eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe;
    (a) Zur-Reaktion-Bringen von der Verbindung f-1 mit Trimethylsulfoxoniumjodid oder Trimethylsulfoxoniumjodid unter der Wirkung einer starken Lauge in einem polaren aprotischen Lösungsmittel, um eine Verbindung f-6 zu erhalten, wobei das polare aprotische Lösungsmittel Dimethylsulfoxid oder N,N-Dimethylformamid ist und die starke Lauge Natriumhydrid oder Kaliumhydrid ist;
    (b) Zur-Reaktion-Bringen von der Verbindung f-6 mit RH in einem unpolaren Lösungsmittel unter einer starken Lauge, um eine Verbindung f-7 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran ist und die starke Lauge Natriumhydrid, Natriumhydroxid oder Kaliumhydroxid ist.
    (c) Unterziehen von der Verbindung f-7 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung f-8 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (d) Oxidieren von der Verbindung f-8 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel, um eine Verbindung f-9 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel m-Chlorperoxybenzoesäure oder Wasserstoffperoxid ist;
    (e) Unterziehen von der Verbindung f-9 mit Hydrazinhydrat einer Hydrazinolyse oder der Verbindung d-6 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung f-10 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist;
    Verfahren IX:
    Figure imgb0119
     wobei R eine lineare C1-6 Alkylgruppe, eine C3-6 Alkenylgruppe, eine C3-6 Cycloalkylgruppe, eine substituierte oder unsubstituierte Phenylgruppe oder eine substituierte oder unsubstituierte, 5- oder 6-gliedrige Heteroarylring-Gruppe ist, die 1 bis 4 Heteroatome aufweist, die unabhängig voneinander ausgewählt sind aus der Gruppe, bestehend aus N, S und O, ist;
    (a) Oxidieren von der Verbindung f-2 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel, um eine Verbindung g-1 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel m-Chlorperoxybenzoesäure oder Wasserstoffperoxid ist;
    (b) Unterziehen von der Benzyl-Schutzgruppe der Verbindung g-1 einer Entschützung in einem unpolaren Lösungsmittel unter der Wirkung einer Lewis-Säure, um eine Verbindung g-2 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist, die Lewis-Säure Bortrichlorid oder Bortribromid ist;
    (c) Zur-Reaktion-Bringen von der Verbindung g-2 mit Diphenyldiazomethan in einem gemischten Lösungsmittel aus einem polaren und unpolaren Lösungsmittel, um eine Verbindung g-3 zu erhalten, wobei das polare Lösungsmittel Methanol oder Ethanol ist; und das unpolare Lösungsmittel Dichlormethan, Ethylacetat oder Tetrahydrofuran ist;
    (d) Oxidieren von der Verbindung g-3 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel für 4 bis 8 Stunden, um eine Verbindung g-4 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel ein Mischung aus Schwefeltrioxid-Pyridin und Dimethylsulfoxid oder ein Mischung aus Oxalylchlorid und Dimethylsulfoxid ist;
    (e) Zur-Reaktion-Bringen von der Verbindung g-4 durch die Wirkung eines Übergangsmetallkatalysators, eines Liganden und einer Wasserstoffquelle in einem polaren Lösungsmittel unter Ar-Schutz, um eine Verbindung g-5 oder g-6 zu erhalten, wobei der Übergangsmetallkatalysator ein Dichlorbis(4-methylisopropylphenyl)ruthenium(II)-Dimer oder ein Dichlor(pentamethylcyclopentadienyl)rhodium(III)-Dimer ist, der Ligand (1R,2R)-(-)-N-(p-Methylbenzolsulfonyl)-1,2-diphenylethylendiamin oder (1S,2S)-(-)- N-(p-Methylbenzolsulfonyl)-1,2-diphenylethylendiamin ist, die Wasserstoffquelle Natriumformiat oder Ammoniumformiat ist und das polare Lösungsmittel N,N-Dimethylformamid ist;
    (f) Unterziehen von der Verbindung g-5 oder g-6 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung g-7 oder g-8 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (g) Unterziehen von der Verbindung g-7 oder g-8 mit Hydrazinhydrat einer Hydrazinolyse oder der Verbindung g-7 oder g-8 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung g-9 oder g-10 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist;
    Verfahren X:
    Figure imgb0120
     wobei in dem oben genannten Schema R1 -OR1, -SR1, -NR2R3 ist; R1 eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe ist; und R2 und R3 jeweils unabhängig voneinander das folgende sind: ein Wasserstoff, eine lineare C1-6 Alkylgruppe, eine verzweigte C3-6 Alkylgruppe oder eine C3-6 Cycloalkylgruppe;
    (a) Oxidieren von der Verbindung d-11 mit einem Oxidationsmittel in einem unpolaren Lösungsmittel für 4 bis 8 Stunden, um eine Verbindung g-11 zu erhalten, wobei das unpolare Lösungsmittel Dichlormethan ist und das Oxidationsmittel eine Mischung aus Schwefeltrioxid-Pyridin und Dimethylsulfoxid oder eine Mischung aus Oxalylchlorid und Dimethylsulfoxid ist;
    (b) Zur-Reaktion-Bringen von der Verbindung g-11 durch die Wirkung eines Übergangsmetallkatalysators, eines Liganden und einer Wasserstoffquelle in einem polaren Lösungsmittel unter Ar-Schutz, um eine Verbindung g-12 oder g-13 zu erhalten, wobei der Übergangsmetallkatalysator ein Dichlorbis(4-methylisopropylphenyl)ruthenium(II)-Dimer oder ein Dichlor(pentamethylcyclopentadienyl)rhodium(III)-Dimer ist, der Ligand (1R,2R)-(-)-N-(p-Methylbenzolsulfonyl)-1,2-diphenylethylendiamin oder (1S,2S)-(-)-N-(p-Methylbenzolsulfonyl)-1,2-diphenylethylendiamin ist, die Wasserstoffquelle Natriumformiat oder Ammoniumformiat ist und das polare Lösungsmittel N,N-Dimethylformamid ist;
    (c) Unterziehen von der Verbindung g-12 oder g-13 und N-Hydroxyphthalimid einer Mitsunobu-Reaktion in einem unpolaren Lösungsmittel, um eine Verbindung g-14 oder g-15 zu erhalten, wobei das unpolare Lösungsmittel Tetrahydrofuran oder 1,4-Dioxan ist;
    (d) Unterziehen von der Verbindung g-14 oder g-15 mit Hydrazinhydrat einer Hydrazinolyse oder der Verbindung g-14 oder g-15 mit Methylamin einer Aminolyse in einem polaren protischen Lösungsmittel, um eine Verbindung g-16 oder g-17 zu erhalten, wobei das polare protische Lösungsmittel Methanol oder Ethanol ist.
EP17830457.2A 2016-07-21 2017-07-18 Monocyclisches b-lactam-eisenträgerkonjugat sowie herstellungsverfahren und anwendung davon Active EP3489234B1 (de)

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US5888998A (en) * 1997-04-24 1999-03-30 Synphar Laboratories, Inc. 2-oxo-1-azetidine sulfonic acid derivatives as potent β-lactamase inhibitors
BR0113861A (pt) * 2000-09-14 2004-01-27 Pantherix Ltd Derivados de ácidos 3-(heteroaril acetamido)-2-oxo-azetidina-1-sulfÈnicos como agentes antibacterianos
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ES2542431T3 (es) 2010-11-29 2015-08-05 Pfizer Inc Monobactamas
UY34585A (es) 2012-01-24 2013-09-02 Aicuris Gmbh & Co Kg Compuestos b-lactámicos sustituidos con amidina, su preparación y uso

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EP3489234A4 (de) 2019-05-29
CN107641119B (zh) 2019-11-08
CN107641119A (zh) 2018-01-30
US20190233407A1 (en) 2019-08-01
WO2018014823A1 (zh) 2018-01-25
US10501454B2 (en) 2019-12-10
US20190382400A9 (en) 2019-12-19
JP6743274B2 (ja) 2020-08-19
EP3489234A1 (de) 2019-05-29
JP2019521173A (ja) 2019-07-25

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